The long-term objective of this proposal is to better understand how host immune systems have and are currently evolving due to parasitism. Genetic variation at adaptively important regions of the genome may be essential to the long term survival and viability of natural populations. Parasite-mediated selection is thought to be an important factor maintaining genetic diversity at the major histocompatibility complex. This region is a highly variable, genetic component of the vertebrate immune system that helps combat macroparasite infections (i.e. cestodes, nematodes, flatworms, and arthropods). Though parasites are often invoked as a potential factor that mediates MHC diversity, relatively few studies have investigated the mechanisms of parasite-mediated selection in natural populations. Many of these studies have difficulty differentiating between the three hypotheses of parasite-mediated selection: heterozygote advantage, rare-allele advantage, and fluctuating selection. In part, this has been due to the fact that to discriminate between heterozygote and rare- allele advantage, we need to determine the association between parasite species and both the host heterozygosity and specific MHC alleles. Further, it is critical to explore the associations between MHC and parasites on both a temporal and spatial scales because otherwise the rare-allele advantage and fluctuating selection hypotheses are difficult to distinguish. Three aims will progress our understanding of the mechanisms of parasite-mediated selection: Aim 1 will characterize MHC class II loci in the Mediterranean gecko (Hemidactylus turcicus). These new gene sequences will not only fill phylogenetic gaps in vertebrate MHC evolution, but will also provide the genetic foundation for a novel model system that can be used to further investigate host-parasite interactions. Aim 2 will test the hypothesis that contemporary selection is acting on MHC class II genes. This will be one of the first studies to test for selection on MHC genes in a widely distributed and locally abundant animal model. Aim 3 will test for parasite-mediated selection by assessing the spatio-temporal variation in multi-species macroparasite infections. The results of this aim will clarify which mechanisms have had the most influence on gecko MHC evolution. Accomplishing our aims will contribute to infectious disease research by providing an explicit test of how parasites affect adaptively important genetic diversity in hosts over space and time. This knowledge will provide perspective on the significance of genetic variation at the MHC to the overall health of natural populations.